Is PTEN p.Pro38Leu (c.113C>T) pathogenic?

PTEN p.Pro38Leu (c.113C>T) is classified Pathogenic in PTEN (ClinVar, Expert panel, 3 submitters; last evaluated 2023-10-11). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Pro38Leu (c.113C>T)?

PTEN p.Pro38Leu (c.113C>T) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Pro38Leu (c.113C>T) in the general population?

PTEN p.Pro38Leu (c.113C>T) is absent from gnomAD v4.1 (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PTEN p.Pro38Leu (c.113C>T)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

PTEN p.Pro38Leu

c.113C>T · rs1064796886 · VCV818421

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):

PS2_VeryStrong PM2_Supporting PS4_Supporting PS3_Moderate PP2 PP3

Curation rationale (ClinGen, verbatim)

NM_000314.8(PTEN):c.113C>T (p.Pro38Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: Two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributor: SCV002757182.1). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.772 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: SCV002757182.1). PM2_P: Absent in gnomAD. PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant = 0.923)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -12.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Pangolin	Δ0.54	gain · loss 0.47 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTEN
Protein: p.Pro38Leu
Coding: c.113C>T
MANE Select: NM_000314
dbSNP: rs1064796886
Type: single nucleotide variant
Location: chr10:87894058 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 38: the phosphatase tensin-type domain

Full PTEN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For PTEN hamartoma tumor syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PTEN p.Pro38His Likely pathogenic ★★★ same residue
PTEN p.Pro38Ser Uncertain significance ★★★ ⚠ same residue
PTEN p.Pro38= Likely benign ★★★ same residue
PTEN p.Pro38Thr Likely pathogenic ★★ same residue
PTEN p.Pro38fs Pathogenic ★ same residue
PTEN p.Pro38Phe Likely pathogenic ★ same residue
PTEN p.Pro38Arg Pathogenic ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pten-p-pro38leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown